ANTIBIOTIC THERAPY, PART I1

0025-7125/01 $15.00

+ .OO

ANTIBIOTIC SIDE EFFECTS

Burke A. Cunha, MD

Antimicrobial side effects present as adverse drug reactions involving one or more organ systems. Although most antibiotics are safe
considering their volume of use, some antimicrobials have the potential
for life-threatening side effects. In general, p-lactams have the least
frequent and least severe side effects. Although any antibiotic is capable
of causing side effects, specific agents from each antibiotic class are more
likely to do so than others. Clinicians should be familiar with the sideeffect potential of individual antibiotics as well as the likelihood of
specific agents being involved in an adverse reaction and should be
familiar with the spectrum of organ involvement associated with particular antimicrobials.
Clinicians have a vast armamentarium of antimicrobials effective
against a wide variety of pathogens. Most antimicrobials have a good
safety profile. Physicians should consider the frequency and severity of
potential adverse effects of antimicrobials when selecting agents for therapy*
INDIVIDUAL VERSUS CLASS SIDE EFFECTS

Most antibiotic-related adverse events are related to specific antimicrobial agents and are not related to antimicrobial classes. Clinicians
often are misled by considering class side effects of antimicrobials instead of assessing the possibility of individual agents being responsible
for the adverse reaction. For example, photosensitizing reactions are

From the State University of New York School of Medicine, Stony Brook, and the Infectious
Disease Division, Winthrop-University Hospital, Mineola, New York

MEDICAL CLINICS OF NORTH AMERICA

VOLUME 85 NUMBER 1 * JANUARY 2001

149

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CUNHA

common with tetracycline but are rare with minocycline or doxycycline.

Similarly, sparfloxacin is associated with photosensitivity reactions
among the quinolones, but other quinolones do not have this problem.
In some cases, class side effects, such as drug fevers among the p-lactam
antibiotics, have clinical relevance, but even with p-lactams there are
important differences. In a patient with a penicillin allergy, cross-reactivity with a cephalosporin is least likely if cefoxitin or cefoperazone is
used. When class side effects exist (e.g., drug fewers with quinolones),
there is great variety within the class of antibiotics (e.g., ciprofloxacin
and trovafloxacin are most likely to be associated with drug fevers,
although any member of the class may be responsible).
Although clinicians should consider class side effects, they need to
be more familiar with specific side effects associated with individual
agents and be familiar with the probability that such side effects may
occur (Tables 1 and 2).

HEMATOLOGIC SIDE EFFECTS

Leukopenia and Thrombocytopenia
Hematologic side effects are common with a wide variety of antimicrobial agents. Isolated cytopenias occur frequently in clinical practice
and may present as neutropenia, anemia, and thrombocytopenia. Leukopenia and thrombocytopenia are the most common hematologic side
effects related to antimicrobial therapy.34p-Lactam antibiotics and the
sulfamethoxazole component of trimethoprim-sulfamethoxazole (TMPSMX) are the two most common causes of isolated leukopenia or thromlS6, ls8 Anemia and pancytopenia are less common.9,
68, 82, Io7
bocytopenia.lS4,

Table 1. ANTIBIOTIC CLASS SIDE EFFECTS

Antibiotic Class

P-Lactams
Sulfonamides
Quinolones
HIV protease inhibitors
Macrolides
Aminoglycosides
Aminoglycosides
P-Lactams
Anti-Pseudomonas penicillins

Side Effects

Drug fever, drug rash

Lipid abnormalities, lipodystrophy
Nausea, vomiting, abdominal discomfort, diarrhea
Ototoxic potential
Nephrotoxic potential
t Prothrombin time/INR
Impaired platelet aggregation

HIV = human immunodeficiency virus; INR = international normalized ratio

ANTIBIOTIC SIDE EFFECTS

151

Table 2. AGENT-SPECIFIC NOT CLASS-SPECIFIC SIDE EFFECTS

Side Effects

Specific Agent

SeiZUreS

Imipenem
Ciprofloxacin
Trovaflovacin

Photosensitivity reactions

Tetracycline
Sparfloxacin

QTc interval prolongation

(23 msec)
Tendinitis, tendon rupture

Ciprofloxacin

Hepatitis ( t SGOT/SGPT)

Trovafloxacin
Grepafloxacin

INH

Acute pancreatitis

Trovafloxacin

Interstitial nephritis
t Prothrombin time/INR

OxaciUin
Trovafloxacin
Temafloxacin

Clinical bleeding

Moxalactam

Non-C. djqicik diarrhea

Trovafloxacin

Anaphylactic reactions to
penicillin

p-lactams

Other Antibiotics
in Same Class

Not meropenem
Not ofloxacin
Not levofloxacin
Not gatifloxacin
Not moxifloxacin
Not doxycycline
Not minocyclie
Not ciprofloxacin
Not ofloxacin
Not levofloxacin
Not gatifloxacin
Not moxifloxacin
Not levofloxacin
Not ciprofloxacin
Not ofloxacin
Not gatifloxacin
Not ofloxacin
Not levofloxacin
Not gatifloxacin
Not moxifloxacin
Not ciprofloxacin
Not ofloxacin
Not levofloxacin
Not gatifloxacin
Not moxifloxacin
Not ethambutol
Not rifampin
Not cycloserine
Not ethionamide
Not pyrazinamide
Not ciprofloxacin
Not ofloxacin
Not levofloxacin
Not gatifloxacin
Not moxifloxacin
Not nafcillin
Not ciprofloxacin
Not ofloxacin
Not levofloxacin
Not gatifloxacin
Not moxifloxacin
Not cefotaxime
Not ceftizoxime
Not cefoperazone
Not ceftazidime
Not cefepime
Not ciprofloxacin
Not ofloxacin
Not levofloxacin
Not gatifloxacin
Not moxifloxacin
Not aztreonam**
Not imipenemt
Not meropenemt

*Rifampin may potentiate increased INH-induced elevations in serum transaminases.

A monobactam; not a p-lactam in terms of cross allergenicity.
tcarbapenems; not p-lactams in terms of cross allergenicity.
SGOT/SGPT = Serum glutamic-oxaloacetic transaminase/senun glutamic-pyruvic transaminase;
INH = isoniazid; INR = international normalized ratio.

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Anemia

The mechanism of antibiotic-related anemia varies according to the

antibiotic being used." For example, p-lactams may cause autoimmune
hemolytic anemia. TMP-SMX may be associated with folate deficiency,
which may result in a megaloblastic anemia.63Eosinophilia may be
associated with any antibiotic causing a drug fever but may occur with
fosfomycin in the absence of drug fever.
Chloramphenicol rarely may cause irreversible aplastic anemia.
Aplastic anemia is an idiosyncratic reaction to chloramphenicol and is
not dose related. Serial hemograms are useful to monitor dose-related,
reversible bone marrow suppression but are of no value in predicting or
preventing chloramphenicol-induced aplastic anemia?, 13, 151, 152 Chloramphenicol-related aplastic anemia occurs with oral, rectal, topical, or intramuscular administration but does not occur if given intravenously.
Immune Platelet Dysfunction

Although certain antimicrobials may decrease the platelet count,

others may interfere with platelet function. Impaired platelet aggregation
occurs most commonly in association with the antipseudomonal penicill i n ~ Antipseudomonal
.~~
penicillin problems with platelet aggregation
are a dose-related side effect.25*
92 The effect on platelets is greatest with
the antipseudomonal penicillins used in high doses (e.g., carbenicillin,
usual dose, 30 g/d). Antipseudomonal penicillins used in lower doses
(e.g., azlocillin, mezlocillin, piperacillin, usual dose, 18 g/d) have less
potential for platelet aggregati~n.~~
Excluding carbenicillin, the antipseudomonal penicillins have little potential for clinical bleeding unless given
to patients with an underlying bleeding diathe~is.~~,
90
Clinical Bleeding

Moxalactam has been associated with clinical bleeding by interfer-

ing with the synthesis of vitamin K-dependent clotting factors and

impairing platelet aggregation. Many antibiotics, particularly the p-lactams, may increase the international normalized ratio (INR) or prothrombin time (PT) by interfering with the synthesis of vitamin K-dependent
clotting
Trovafloxacin, among the quinolones, frequently increases the PT or INR; other quinolones do not show this effect. Formerly, it was thought thaf the methyltetrathiozole (MTT) side chain was
a structural marker of bleeding potential among p-lactam antibiotics.
Cephalosporins with a MTT side chain include cefamandole, cefoperazone, and cefotetan, but antibiotics with a MTT side chain have not
caused clinical bleeding. Elevations of the INR or PT normalize rapidly
after discontinuation of the antibiotic or the administration of intramuscular vitamin K by weekly intramuscular injection. Clinical bleeding

ANTIBIOTIC SIDE EFFECTS

153

relates to the severity of the clinical illness, not to the MTT side chain
(no MTT side chain). In a study in the intensive care setting, cefoxitin
was associated most frequently with clinical bleeding. The authors concluded that the potential for bleeding is related to severity of illness and
not to any particular structural component of the antibiotic (e.g., the
MTT side chain). Based on this study and the experience of others, most
clinicians give intensive care unit (ICU) patients prophylactic intramuscular injections of vitamin K on a weekly basis to minimize potential
bleeding problems (Table 3).
HYPERSENSITIVITY SIDE EFFECTS

Drug Fever

Drug fevers are the most common antibiotic-mediated hypersensitivity side effect. Drug fevers account for 10% to 15% of unexplained
fevers in hospitalized patients in the United States. Drug fevers may
occur with any antibiotic but are particularly common with p-lactams
and sulfonamides and may occur with any antiviral, antifungal, or
antiparasitic medication.l, 155 Drug fevers are defined as hypersensitivity
reactions to medications whose primary clinical expression is that of
fever without rash. Drug fevers are febrile reactions to medications
that are mediated in the liver. Transient mild elevations of the serum
transaminases are regular clinical features of drug fevers.54
It is a common misconception that most drug fevers are antibiotic
related. Most drug fevers are caused by nonantibiotics and are particularly common with diuretics, stool softeners, antiseizure medications,
antiarrhythmics, sedatives, antihypertensives, and pain medications. If
the clinician can exclude nonantibiotic medications, antibiotics should
be considered, keeping in mind the relative frequency of individual
antimicrobial agents causing drug fever. Laboratory abnormalities associated with drug fever may suggest an infectious process in the airway
(e.g., the white blood cell count often is elevated with a left shift).
Eosinophils usually are present in the peripheral smear of patients with
drug fevers, but eosinophilia is less common. The diagnosis of drug
fevers should be entertained in patients with obscure fevers with negative blood cultures, after other explanations for the fever have been
excluded. Drug fever is a syndromic diagnosis characterized by temperatures greater than or equal to 102F (usual range, 102F to 106F) and
relative bradycardia in patients not on P-blocker therapy, with arrhythmias or with a pacemaker. Relative bradycardia is a constant finding in
patients with drug fevers greater than or equal to 102F. Such patients
also look relatively well for the degree of fever and do not have shaking
chills unless they have been given antipyretics.88
Transient elevations of the serum transaminases accompanied by
eosinophils in the peripheral smear in a patient with negative blood
cultures, excluding contaminants, are suggestive of drug fever. The
diagnosis of drug fever is confirmed by observing a decrease in the

i2

CI

Common

P-Lactams

Sulfonamides
Nalidixic acid

INH

G6PD hemolytic anemia

Sideroblastic anemia

Chloramphenicol
Amphotericin B

P-Lactams
Flucytosine
Pyrimethamine
TMP-SMX
AZT
Vancomycin

Autoimmune hemolytic anemia

Anemia
Nonhemolytic anemia

Neutropenia

Side Effects

Table 3. HEMATOLOGIC SIDE EFFECTS

TMP-SMX
INH
Indinavir
Ceftriaxone
Primaauine
DapsoAe
Th4P-SMX
Nitrofurantoin
P-Lactams
Pyrazinamide

AZT
Ganciclovir
Indinavir
Ribavirin
Adefovir

Anemia secondary to chloramphenicol is dose

related. Anemia is the first sign of
chloramphenicol marrow depression, is readily
reversible when chloramphenicol is discontinued,
and is not a precursor of aplastic anemia
Anemia secondary to amphotericin B is due to
inhibition of erythropoietin
Clinically, rarely due to cephalosporins

Comments

P-Lactams and anti-HIV drugs are the most common

cause of neutropenia. WBCs rapidly return to
normal after the causative drug is discontinued
Penicillins more commonly cause leukopenia than
cephalosporins

Uncommon

Quinolones
Indinavir
Lamivudine (3TC)
ddI
ddC
Dapsone
Ganciclovir
Griseofulvin
Capreomycin
Chloramphenicol
Aztreonam
Imipenem
Amantadine
Piperacillin/
Tazobactam

m
m

CI

Anv B-Lactam

Trovafloxacin

INR/urothrombin time

Carbenicillin

Moxalactam
Temafloxacin

Clinical bleeding

human immunodeficiency virus; WBCs

TMP is a folate antagonist, and TMP may result in

megaloblastic anemia
Chloramphenicol aplastic anemia may occur after
only 1 dose. Does not occur with intravenous
chloramphenicol but may occur with oral,
intramuscular, rectal, or topical ocular
administration
Any antibiotic causing drug fever (except
pentamidine) may also cause eosinophilia
Platelet counts rapidly revert to normal after
offending agent is discontinued. A clue to druginduced thrombocytopenia is the reactive
thrombocytosis after platelet counts return to
normal
Chloramphenicol-associated, dose-related bone
marrow suppression sequentially depresses red
cells (anemia) followed by white cells (leukopenia)
and lastly platelets (thrombocytopenia).
Pancytopenia is a dose-related reversible effect of
prolonged chloramphenicol use
Dose-dependent side effect with antipseudomonal
penicillins (e.g., carbenicillin 30 g/d). Usually,
clinically unimportant with newer
antipseudomonal penicillins, ticarcillin, azlocillin,
mezlocillin, or uiueracillin, that are used in lower
dosage (e.g., 18&d)
Clinical bleeding is not related to the MTT side
chain. No bleGding with cefamandole,
cefoperazone, or cefotetan
Clinical bleeding is related to the severitv of illness
(e.g., ICU pativents on cefoxitin)
t INR/hmothrombinemia most common with
' trovaflokacin, cefoperazone, and cefotetan

TMP-SMX = Trimethoprim-sulfamethoxazole;
AZT = azidothymidine; ddI = dideoxyinosine; ddC = dideoxycytidine; HIV
white blood cells; INH = isoniazid; GGPD = glucose-6-phosphate dehydrogenase; INR = international normalized ratio.

Cef triaxone

Antipseudomonal
penicillins
Moxalactam

Impaired platelet aggregation

TMP-SMX
ddI

Chloramphenicol

Flucytosine
Linezolid

TMP-SMX

Fosfomycin
Nevirapine
Pyrimethamine
Ganciclovir
AZT
Chloramphenicol

Pancytopenia

Thrombocytopenia

TMP-SMX
P-Lactams
P-Lactams

Chloramphenicol

Aplastic anemia

Eosinophilia

TMP-SMX

Megaloblastic anemia

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Drug Fever
Clinical Features

History
Many individuals are atopic
May have been on sensitizing medication for days or years
Signs
Low-grade to high-gradefevers (102F 2 106"F, but usually 102 OF-1 04F)
Relative bradycardia with temperatures 2 102F
Appear inappropriately well for degree of fever
Determination of relative bradycardia
Inclusive criteria
Adult with temperature 2102F
Pulse must be taken simultaneously with the temperature
Exclusive criteria
Patient must not be on p-blocker medications
Patient has no arrhythmia, second-degree or third-degree heart block, or pacemaker rhythm
Exclude other disorders associated with relative bradycardia (e.g., Legionella,
psittacosis, Q fever, typhoid fever, typhus, malaria, babesiosis, leptospirosis, yellow fever, dengue fever, Rocky Mountain spotted fever, central nervous system lesions, lymphomas, and factitious fever)
Normal temperature-pulserelationships
Temperature and appropriate pulse response (beatslmin)
106F (41.1"C) 150
103F (395C) 120
105F (40.6%) 140
102F (38.9%) 110
104F (40.0"C)
130
Laboratory tests
Elevated white blood cell count (usually with left shift)
Eosinophils almost always present in peripheral blood, but eosinophilia (low
grade) is uncommon (520%)
Elevated erythrocyte sedimentation rate is present in most cases (may be 2100
mmlh) but usually in the range of 40-60 mmlh)
Transient, mild elevations of serum transaminases (approximately 90%) usually
5 2 x normal occur early

Common

Drugs Implicated in Drug Fever

Common

Asparaginase
Barbiturates
Methyldopa
Penicillins
Cephalosporins
Phenytoin
Procainamide
Quinidine
Sulfonamides (including sulfacontaining laxatives)
Diuretics
Narcotics
Sleep medications

Allopurinol
Azathioprine
Hydralazine
Iodides
lsoniazid
Nonsteroidalantiinflammatory drugs
p-Blockers
Calcium channel blockers
Angiotensin-converting
enzyme inhibitors

Uncommon
Aminoglycosides
Macrolides
Tetracyclines
Clindamycin
Chloramphenicol
Quinolones
Vancomycin
Linezolid

ANTIBIOTIC SIDE EFFECTS

157

temperature after the offending medication is withdrawn. The temperature with drug fever decreases to near normal within 72 hours after the
sensitizing medication is discontinued if a rash is not present. If a
hypersensitivity reaction causing the drug fever is allowed to continue
without discontinuing the medication, the patient may develop a drug
rash.88 The accompanying box presents information on clinical drug
fever.

Drug Rash

Drug rash may be caused by any of the medications causing drug

fever but is particularly common with p-lactams or the sulfamethoxazole
component of TMP-SMX.28,63 Drug rashes are a cutaneous manifestation
of a drug hypersensitivity reaction.127,
lZ8Nonantibiotic medications are
common causes of drug rash and should be sought before considering
an antimicrobial explanation for the rash. Acute drug rashes usually are
accompanied by all of the clinical and laboratory features of drug fever.
Drug fever rashes involve the entire body and may involve the palms
and the soles. The spectrum of cutaneous manifestations range from
maculopapular eruptions to the Stevens-Johnson syndrome. Drug rashes
most frequently are maculopapular but may have a petechial component. Virtually all drug rashes are pruritic at some stage. Drug-induced
exanthems may be differentiated from the maculopapular rash of contact
dermatitis by the distribution of the rash.31Patients with contact dermatitis do not have any of the features of a drug fever or rash and have a
rash that is limited to certain areas and does not involve most of the
body.lO, 19,20,22, 54,141
Red neck or red man syndrome is a histamine-mediated reaction to
the rapid infusion of vancomycin and does not represent a true allergic
reaction to vancomycin.l,13,34, 65*115, l5O, 153 Vancomycin may be given safely
to patients with red man or red neck syndrome. This reaction to vancomycin may be eliminated or minimized if the drug is given slowly
intravenously.

Anaphylactic Reactions

Among antimicrobials, p-lactams most frequently are associated

with anaphylactoid reactions.s, 86 The sulfamethoxazole component of
TMP-SMX also is a common cause of antibiotic-induced anaphylaxis.
Although structurally similar to p-lactams, monobactams and carbapenems should not be considered as p-lactams." Aztreonam, imipenem, and
meropenem may be used safely in patients with anaphylactoid reactions
to penicillin (Table 4).lL 36.43.79,87, 113,125,134,135

Antivirals
Antifungals
Antiparasitics
Quinolones
-

Quino1ones
Delavirdine
Nevirapine
Efavirenz

P-Lactams
Sulfonamides (TMP-SMX)

Drug rash

Uncommon

P-Lactams
Sulfonamides (TMP-SMX)

Common

Drug fever

Side Effects

Table 4. HYPERSENSITIVITY SIDE EFFECTS

The TMP component of TMP-SMX

never is responsible for allergic
reactions with TMP-SMX; it is
always related to the sulfa
component-SMX
Quinolones are an uncommon cause of
drug fever; however, among the
quinolones, ciprofloxacin and
trovafloxacin most often cause drug
fevers
Cutaneous drug reactions to p-lactams
often have a raised papular
component
Cutaneous sulfa rashes usually are
morbilliform
Patients with allergic reactions to
cephalosporins are least likely to
cross-react with cefoperazone or
cefoxitin among the cephalosporins
Aztreonam, imipenem, and meropenem
may be used safely in penicillin
allergies

Comments

Systemic lupus erythematosus.

Serum sickness

P-Lactams

Phototoxicity reactions

SLE

INH

Minocycline
Tetracycline
Sparfloxacin

P-Lactams
Efavirenz
Delavirdine
Nevirapine
Nitrofurantoin
Grieseofulvin
Pyrazinamide
Pefloxacin
Lomefloxacin
Grieseofulvin
Chloroquine
Primaquine
Any antibiotic

Sulfonamides (TMP-SMX)

E. rnultiforrne, Stevens-Johnson
syndrome

Drug-induced SLE

TMP-SMX

P-Lactams

Anaphylaxis

Usually occurs approximately 2 weeks

after drug is discontinued
Serum sickness reactions are
characterized by fever and
arthralgias

Drug-induced SLE does not affect the

central nervous system or kidneys
Doxycycline and minocycline rarely
cause photosensitivity reactions
Phototoxicity reactions to sparfloxacin
may occur days after the drug is
discontinued

Aztreonam, imipenem, and meropenem

do not cross-react with p-lactams
and may be used in patients with
anaphylactic reactions to p-lactams
Sulfonamides are the most common
antibiotic cause of E. rnultiforrne

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Serum Sickness
Serum sickness reactions may occur with any medication and when
associated with antimicrobial therapy usually are due to p-lactams.
Serum sickness symptoms usually occur 2 weeks after exposure to
the causative medication and are accompanied by nonspecific systemic
findings that include low-grade fevers and arthralgias and myalgias.
Serum sickness should be suspected in patients with low-grade fevers
and arthralgias occurring 2 weeks after antimicrobial therapy and may
be confirmed by showing a decrease in the serum complement in such
patients after other disorders have been excluded.77,90, lZ4
Photosensitivity Reactions
Photosensitizing reactions commonly occur with tetracycline and
sparfloxacin. Photosensitivity reactions are rare with doxycycline and
minocycline as well as the other fluoroquinolones. Less commonly, perfloxacin and lomefloxacin have been associated with photosensitizing
reactions. The photosensitizing reactions that occur with sparfloxacin
may occur for 1 week after cessation of the medication. If sparfloxacin
is used, patients are advised to use sunscreens or to avoid direct sunlight
for at least 1 week after sparfloxacin therapy.18,40, 90, 143
Drug-Induced Systemic Lupus Erythematosus
Many medications may induce a systemic lupus erythematosus-like
syndrome. Antibiotics are a rare cause of drug-related systemic lupus
erythematosus. Antibiotics implicated in drug-induced systemic lupus
erythematosus include minocycline, isoniazid (INH), nitrofurantoin, and
griseofulvin.
NEUROLOGIC SIDE EFFECTS
Antimicrobials are responsible for a wide spectrum of neurologic
adverse reactions. The most serious neurologic side effects include encephalitis, seizures, neuromuscular blockage, and muscular spasticity.
Encephalopathy
Encephalopathy is a frequent side effect of trovafloxacin therapy
and has been reported in association with clarithromycin. As with nonantimicrobial medications, the antibiotic-induced encephalopathy clears
16, 58, lo5
rapidly after the medication is dis~ontinued.'~,

ANTIBIOTIC SIDE EFFECTS

161

Seizures

Antibiotic-induced seizures usually are due to ciprofloxacin, imipenem, or trovafloxacin.lo5A wide variety of medications have been
implicated in seizures but less c~mmonly.~O,~~
The ability of an antimicrobial to induce seizures depends on the seizure threshold of the patient
and the neuroexcitatory effect of the medication on central nervous
system receptors.30,14*,
Although ciprofloxacin, imipenem, and trovafloxacin do not cross the blood-brain barrier in high concentrations,
they have been implicated in antibiotic-induced seiz~reses.9~~
Seizures
usually resolve promptly after the offending medication is withdrawnz6,
90, lol Levofloxacin and meropenem do not predispose to or cause seizures.", 55, 57

Neuromuscular Blockade

Neuromuscular blockade may occur after aminoglycoside therapy

if large amounts of the aminoglycoside are absorbed (e.g., aerosolized
instillation into the lungs or when used for peritoneal lavage). Clindamycin, when used in peritoneal lavage, may induce transient respiratory
arrest. Such patients should receive ventilatory support until neuromuscular transmission returns to normal and the patient resumes unassisted
ventilation.

Peripheral Neuropathy

Peripheral neuropathy most commonly is associated with INH toxicity but may occur with griseofulvin or cycloserine. Pyridoxine should
be given along with INH in antituberculous regimens to prevent INHinduced peripheral neuropathy. Long-term high-dose nitrofurantoin
therapy in patients with renal insufficiency also may result in peripheral
ne~ropathy.'~,

Muscular Tremors and Myalgias

Muscular tremors and spasticity traditionally have been associated

with amantadine therapy. The parkinsonian-like symptoms of amantadine are most common in the elderly and may be prevented or eliminated by decreasing the dose in elderly patients?O Trovafloxacin may
cause isolated muscular tremors or spasticity involving the entire
body.105,
lZ9Painful myalgias has been an infrequent, but disturbing, side
effect of quinupristin/dalfopristin.

162

CUNHA

Ototoxicity

Ototoxicity is seen most commonly with aminoglycosides or parenteral erythromycin therapy. Ototoxicity may be cochlear or vestibular,
but only aminoglycosides have been associated most commonly with
both types of toxicity. Deafness resulting from cochlear toxicity may be
irreversible and is associated with prolonged, highly elevated aminoglycoside serum levels. Deafness may follow rapid infusions of intravenous
erythromycin. In contrast, dizziness or vestibular toxicity is associated
with minocycline. Minocycline's vestibular toxicity is due to high lipid
solubility, which results in high minocycline concentrationsin the cells of
the vestibular apparatus. Symptoms resulting from minocycline-induced
dizziness usually clear within a few days after minocycline is discontinued.
Blindness

Blindness resulting from antimicrobials is unusual. Ethambutol most

commonly is associated with a decrease in visual acuity, which may lead
to blindness. Ethambutol's ocular toxicity may occur in patients receiving greater than or equal to 25 mg/kg of ethambutol as part of an
antituberculous regimen but does not occur if 5 1.5 mg/kg is used.
Serial ophthalmologic examinations usually are not needed in patients
receiving ethambutol unless they have pre-existing eye disease. Patients
can screen for visual toxicity by noticing a change in visual acuity when
reading books or newspapers and report this to their physician. Patients
experiencing such changes should be referred to a neurologist for ophthalmologic evaluation (Table 5).13,90
PULMONARY SIDE EFFECTS

Pulmonary drug reactions are an uncommon side effect of antimicrobial therapy. The presence of drug-induced pulmonary side effects
should suggest a nonantimicrobial explanation.
Acute Pulmonary Reactions

The most common pulmonary side effects resulting from antibiotics

are a flulike illness often seen early after the initiation of rifampin
the rap^.^ The other antimicrobial reactions directly involving the lung
most frequently are due to nitrofurantoin. Nitrofurantoin pulmonary
reactions may be acute or chronic, and these clinical manifestations
are dissimilar. Acute pulmonary reactions resulting from nitrofurantoin
usually result in fever accompanied by pulmonary infiltrates with varying degrees of respiratory insufficiency, pleural effusions, and peripheral

ANTIBIOTIC SIDE EFFECTS

163

eosinophilia. Acute nitrofurantoin pulmonary reactions are transient and

are readily reversible when the antimicrobial is discontinued.
Chronic Pulmonary Reactions
Chronic pulmonary reactions secondary to nitrofurantoin may result
in pulmonary fibrosis, which is irreversible. Chronic pulmonary reactions secondary to nitrofurantoin are not characterized by fever, peripheral eosinophilia, or pleural effusions but are a chronic, slowly progressive inflammatory process. Chronic pulmonary nitrofurantoin toxicity
occurs in patients with renal insufficiency receiving prolonged high
doses of nitrofurantoin. Such patients should never receive nitrofurantoin in the presence of renal insufficiency and should not be given the
medication over prolonged periods without dosing modifications. Given
the volume of use for nitrofurantoin, acute pulmonary reactions are
relatively uncommon, and chronic reactions are rare.12 Chronic pulmonary toxicity secondary to nitrofurantoin may be avoided by using
nitrofurantoin only for short courses of therapy in patients with advanced renal insufficiency, then using a reduced dose commensurate
with the patients renal function (Table 6).13
CARDIAC SIDE EFFECTS
Prolonged QT, Interval
Ventricular arrhythmias may occur by direct effect of the drug on
myocardial irritability. A prolonged QTc interval may result in ventricular arrhythmias (e.g., torsades de pointes)jl The antimicrobials most
commonly associated with prolongation of the QT, interval include IV
erythromycin, terbinafine, and some quinolones. QTcprolongation occurs
rapidly after an antibiotic is administered, and normalization of the QT,
interval occurs after the drug is withdrawn.149Quinolones that prolong
the QT, interval 2 3 msec should not be used together with other
medications that cause QTc prolongation or in patients with cardiac
arrhythmias of conduction abnormalities.
Heart block is an unusual manifestation of antimicrobial therapy,
and if present, a nonantimicrobial explanation should be sought. Myocarditis is a rare complication of nevirapine therapy.
Hypotension
Antimicrobial-induced hypotension commonly occurs with pentamidine. Trovafloxacin and amphotericin B also may induce hypotension
(Table 7). Trovafloxacin-induced hypotension may be prolonged (i.e., 12
to 24 hours) and require fluids and pressors to maintain blood pressure
organ perfusion until trovafloxacin is metabolized and eliminated.96
Text continued on page 170

Erythromycin
Clarithromycin
Itraconazole
Azithromycin
Griseofulvin
Delavirdine
Saquinavir
Abacavir
Efavirenz
Foscamet
Polymyxin B
Trovafloxacin

Cycloserine
Foscamet
Ethambutol
Amantadine
Ethionamide
Ganciclovir
Polymyxin B

TMP-SMX

Trovafloxacin
Clarithromycin

Aseptic meningitis

Encephalopathy

Uncommon

TMP-SMX
Cycloserine

Common

Headache

Side Effects

Table 5. NEUROLOGIC SIDE EFFECTS

TMP-SMX often is overlooked as a cause of

aseptic meningitis
Trovafloxacin may cause muscle spasms of
the neck (meningismus) mimicking
meningitis
Trovafloxacin central nervous system side
effects include mental confusion and
encephalopathy, which clear when
trovafloxacin is discontinued

TMP-SMX may cause headache or aseptic

meningitis

Comments

Amantadine
Rifampin
Foscamet
Ganciclovir
Metronidazole
TMP-SMX
Nalidixic acid
Erythromycin
TMP-SMX
Nitrofurantoin
Nalidixic acid
Polymyxin B
Polymyxin B
Clindamycin
Erythromycin

Ciprofloxacin
Imipenem
Trovafloxacin
Cycloserine
Acyclovir
Valcyclovir
Famciclovir

Metronidazole
Amantadine

Aminoglycosides
Capreomycin

Cycloserine

Seizures

Cerebellar ataxia

Myasthenic syndrome,
neuromuscular blockade

Depression

Ethionamide

Cycloserine
Ofloxacin

Ciprofloxacin

Neuroexcitatory symptoms

May occur with aminoglycosides/polymyxin

B administered to the lungs by aerolizer or
with aminoglycoside/clindamycin by
peritoneal lavage
Disappears after drug withdrawal
Neuromuscular blockage may follow
massively absorbed quantities of drug
interfering with neuromuscular
transmission
Disappears after drug withdrawal
Table continued on following page

Disappears after drug withdrawal

Neuroexcitatory effects may be minimized by

taking antibiotics with neuroexcitatory
effects in the morning rather than in the
evening
Most common causes of antibiotic-related
seizures are ciprofloxacin, imipenem, and
trovafloxacin
Levofloxacin and meropenem do not cause
seizures

Severe myalgias

Muscular tremors, spasticity

Pseudotumor cerebri (benign

intercranial HT)
Peripheral neuropathy

Psychosis

Side Effects

Amantadine
Trovafloxacin
Foscamet
@mupristim/dalfopristin

INH
Griseofulvin
Cycloserine
Trovafloxacin

Foscarnet
Ethionamide
Efavirenz
Tetracycline

Common

Table 5. NEUROLOGIC SIDE EFFECTS (Continued)

Nitrofurantoin
Ethionamide
Polymyxin B
Ethambutol
Metronidazole
Foscamet
d4T
Lamivudine (3TC)
ddC
dd1
AZT
Ganciclovir

Trovafloxacin
Amprenavir

Uncommon

Although severe myalgias are uncommon,

they are prolonged/very painful when they
occur

Parkinsonian symptoms reversible when drug

is discontinued

INH-induced peripheral neuropathy may be

prevented by concomitant administration of
pyridixine
Peripheral neuropathy owing to
nitrofurantoin is associated with prolonged
high-dose therapy in patients with renal
insufficiency and may be permanent

Disappears after drug withdrawal

Comments

Aminoglycoside
Efavirenz
Abacavir
Chloroquine
Ganciclovir

Amprenavir

h4inocycline
Streptomycin

Ethambutol

Indinavir
Amprenavir

Blindness

Dysphagia
Circumoral paresthesias

NSAIDs = Nonsteroidal anti-inflammatory drugs.

Dizziness (vestibular)

Vancomycin
Capreomycin
Viomycin

Aminoglycosides
Erythromycin

Ototoxicity
Deafness (cochlear)

Reversible when drug is discontinued

Deafness from erythromycin may follow

rapid intravenous infusion
Aminoglycoside-associated cochlear deafness
is usually irreversible
Aminoglycoside deafness may occur after
prolonged, highly elevated peak serum
concentrations
Vestibular toxicity from minocycline is due to
its high lipid solubility and concentration in
vestibular cells
Among the aminoglycosides, streptomycin
has the greatest otologic potential
Ganciclovir may cause retinal detachment
Ethambutol causes red-green color blindness
Ethambutol causes dose-dependent visual
acuity in high doses; does not occur with
daily doses of 4 5 mg/kg
Ethambutol may cause central scotoma

Rifampin

Nitrofurantoin

Pleural effusions

Nitrofurantoin

Nitrofurantoin

Common

Flu-like illness

Chronic pulmonary reactions

Pulmonary fibrosis

Acute pulmonary reactions

Pulmonary infiltrates, acute
respiratory insufficiency

Side Effects

Table 6. PULMONARY SIDE EFFECTS

Abacavir
Efavirenz

Sulfonamides

Amphotericin B

Uncommon

Prolonged high-dose nitrofurantoin in

patients with renal insufficiency rarely may
cause pulmonary fibrosis
Chronic nitrofurantoin pulmonary toxicity
may be irreversible. Fever, peripheral
eosinophilia, and pleural effusions are not
features of chronic nitrofurantoin
pulmonary reactions
Promptly disappears when rifampin is
discontinued
Any antibiotic causing drug-induced systemic
lupus erythematosus may cause pleural
effusions
Pleural effusions are a feature of acute
nitrofurantoin pulmonary reactions that
clear rapidly when the drug is discontinued

Acute lung reactions are more common than

chronic and are characterized by fever,
pleural effusion, and migratory pulmonary
and peripheral eosinophilia. Acute
pulmonary effects promptly disappear
when drug is discontinued
Amphotericin B may cause acute pulmonary
infiltrates in leukopenic patients

Comments

Efavirenz

Amphotericin B lipid formulations

Nevirapine

May occur as part of DRESS syndrome (drug rash, eosinophilia,

and systemic symptoms)

Pentamidine-induced and amphotericin B-induced hypotension

is transient and corrects after the infusion is terminated
Trovafloxacin-induced hypotension may occur after a single dose
and may be prolonged (approximately24 h) and require
intravenous fluids and pressors to restore blood pressure

Heart block reverses when drug is discontinued

Amphotericin B

Hypertension
Myocarditis

Hypotension

Heart block
Vancomycin
Antiparasitics
Miconazole

Sparfloxacin causes the greatest QT, interval prolongation

Amphotericin B and vancomycin are rare causes of cardiac arrest

Rapid intravenous infusion of penicillins with high potassium
contact may result in hyperkalemia-inducedarrhythmias

Comments

Indinavir
Penicillins
Vancomycin
Amphotericin B
Itraconazo1e

Uncommon

Erythromycin
Terbinafine
Sparfloxacin
Grepafloxacin
Moxifloxacin
ddI
Quinine
Pentamidine
Trovafloxacin
Amphotericin B

Erythromycin

AZT

Common

Prolonged QT, interval

( 2 3 msec)

Ventricular arrhythmias

Side Effects

Table 7. CARDIAC SIDE EFFECTS

GASTROINTESTINAL SIDE EFFECTS

Nausea and Vomiting

Many drugs are associated with nausea and vomiting, and antimicrobials are no exception. As a group, antiretrovirals commonly are
associated with nausea, vomiting, or abdominal discomfort, which may
be so severe as to lead to cessation of the medication. Among antibiotics,
the macrolides are the least well tolerated when given by the oral route.
Clarithromycin is associated with gastric discomfort and taste perversion
(i.e., metallic taste). The new formulations of clarithromycin (Biaxin XL)
and amoxicillin/clavulanate have minimal gastrointestinal side effects.1569,83,157
Tetracyclines usually are well tolerated when administered orally,
but doxycycline and minocycline may cause gastrointestinal upset if
given on an empty stomach. Although tetracycline should be administered without food (i.e., 1 hour before or 2 hours after a meal), doxycycline and minocycline always should be administered with food. Giving
doxycycline using the tablet formulation with food all but eliminates
gastrointestinal problems in most patients.49,50
Non-Clostridium difficile Diarrhea

Antibiotic-induced diarrhea may be due to a variety of mechanisms.

C. dzjicile diarrhea should be viewed as being an irritative diarrhea and
is caused by change in the colonic flora, by having a high osmotic load,
or by being irritative to the colon in high concentrations.35Usually orally
administered antibiotics that are absorbed (i.e., 290%) in the proximal
gastrointestinal tract are not associated with nausea or vomiting or
diarrhea (irritative diarrheas).
Antibiotic-induced non-C. dijicile diarrhea is associated most commonly with the macrolides.4.35 Non-C. dificile diarrhea also commonly
may accompany therapy with ampicillin, amoxicillin-clavulanic acid,
ceftriaxone, macrolides, or trovafloxacin.80,83, 117 Ampicillin causes diarrhea by being irritative to the colon in high concentration because it is
not absorbed efficiently from the proximal gastrointestinal tract. Amoxicillin is well tolerated by the proximal gastrointestinal tract and is not
associated with irritative diarrheas?
Non-C. dificile antibiotic-associated diarrheas are frequently accompanied by Cundidu infection of the throat, urine, or vagina as a result of
disruption of the colonic microflora. Among the cephalosporins, ceftriaxone induces the most substantial changes in the colonic microflora, often
resulting in diarrhea., 11* Ceftriaxone-induced non-C. dificile diarrhea
is not due to the high intraluminal concentrations of ceftriaxone or
ceftriaxones enterohepatic biliary
Other antibiotic drugs
with an enterohepatic circulation with high intracolonic concentrations

ANTIBIOTIC SIDE EFFECTS

171

(nonirritative) include nafcillin and do~ycycline.~~,

49 These antibiotics do
not cause non-C. dificile irritative diarrheas. The incidence of ceftriaxone
diarrhea in children is approximately 50% but is much less in adults.
Closfridium difficile Diarrhea

Some but not all antibiotics may cause C. difficile diarrhea. The plactams are the most important antibiotic class causing this adverse
event. Antibiotic-associated C. dificile diarrhea may occur weeks after
the antibiotic exposure. Quinolones Doxycycline, and Meropenem are
rare causes of C. difficile diarrhea.15, 148
Acute Pancreatitis

Acute chemical or clinical pancreatitis has been associated with pentamidine

Alternately, antiretrovirals and TMP-SMX have been implicated as a cause of antimicrobial-induced pancreatitka, 90 Trovafloxacin
may induce chemical or clinical acute pancreatitis. (Table 8):7, 71
HEPATIC SIDE EFFECTS
Drug-Induced Hepatitis

Elevations in the serum transaminases traditionally have been associated with INH in antituberculous therapy. Mild and transient elevations of serum transaminases are common with a wide variety of drugs
and are particularly common with antiretroviral therapy.lZ6Oxacillin is
the most common p-lactam associated with antibiotic-induced hepatitis,
but nafcillin, even with an enterohepatic circulation, is a rare cause
of antibiotic-induced hepatitis. Elevations in the serum transaminases
secondary to trovafloxacin may occur after a single oral or intravenous
dose. Patients receiving trovafloxacin should be monitored with daily
transaminase determinations to detect these abrupt elevations in the
serum transaminases. If trovafloxacin is discontinued, serum transaminase elevations return to normal rapidly in most patients, but in patients
with pre-existing liver disease, trovafloxacin-induced elevations of serum transaminases take days to weeks to normalize.59, 133, 13*, 139
Cholestasis

Cholestasis is more common with nonantimicrobial medications.

Among antimicrobials, erythromycin, nitrofurantoin, and thiabendazole
are the most common causes of antimicrobial-induced cholestasis. Tetra-

C. difficile diarrhea
Acute pancreatitis

Diarrhea
Non-C. dzfficile
diarrhea

Nausea, vomiting

Side Effects

P-Lactams
Trovafloxacin
Pentamidine

Clarithromycin
Erythromycin
Azithr omycin
Ampicillin
Amoxicillii-clavulanic acid
Ceftriaxone
Trovafloxacin

N e1finavir
Ritonavir
Ribavirin
Delavirdine
Foscamet
Ind inavir
Saquinavir
Abacavir
Etionamide
AZT
ddI
d4T
3TC
Clarithromycin
Erythromycin
Azithromycin

Common

Table 8. GASTROINTESTINAL SIDE EFFECTS

Uncommon

Trovafloxacin
TMP-SMX
Nitrofurantoin
ddC
Lamivudine (3TC)
ddI
d4T

Tetracyclines
Clindamycin
Flucytosine

TMP-SMX
Metronidazole
Doxycycline
Itraconazole
Ketoconazole
Ganciclovir
Terbinafine
Methenamine salts
Fosfomycin

Comments

Because amoxicillin and doxycycline are well absorbed

in the proximal gastrointestinal tract, they do not
cause irritative diarrheas owing to high intraluminal
concentrations of antibiotics
Ceftriaxone causes non-C. dificile diarrhea by inducing
profound changes in the intestinal flora. Non-C.
dificile ceftriaxone diarrhea occurs in approximately
50% of children and is less common in adults
May occur weeks after antibiotic exposure
Trovafloxacin-induced pancreatitis may be chemical (e.g.,
t amylase and lipase) or clinical ( t amylase and
lipase with abdominal pain)
Linezolid may cause T lipase or amylase, causing
chemical but not clinical pancreatitis

Protease inhibitors, nucleoside analogue, and macrolides,

particularly clarithromycin, are the most common
causes of antibiotic-associated or antiviral-associated
nausea, vomiting, and abdominal discomfort
Rapid intravenous infusion of imipenem may cause
nausea and vomiting
Quinupristin-dalfopristin causes T SGPT and less
commonly SGOT

ANTIBIOTIC SIDE EFFECTS

173

cycline is hepatotoxic in pregnancy and is dose related. Tetracycline

hepatotoxicity occurs with doses greater than or equal to 2 g/d. Doxycycline and minocycline are not hepatotoxic since their usual daily dose is
much less than 2 g/d (i.e., 200 to 400 mg/d).13,23,47,89,99
Hepatic Necrosis

Acute hepatic necrosis and liver failure may occur in association

with PAS, ketoconazole, or trovafloxacin therapy?O Fatal hepatic necrosis
secondary to trovafloxacin appears to be due to an idiosyncratic (i.e.,
not dose related) hypersensitivity rea~tion.~
48 Trovafloxacin liver failure
has necessitated liver transplantation and has resulted in death in several
cases?8 Because of the potential of fatal hepatic necrosis, trovafloxacin
should not be used.Q 139 Nitrofurantoin rarely causes chronic active
hepatitis (Table 9).60,
NEPHROTOXIC SIDE EFFECTS
Nephrotoxicity

Nephrotoxicity may be manifested as glomerular or tubular toxicity

and may be due to a variety of anti-infectious agents.3,7, 44, ~ 4 ,147
Tubular toxicity is more common and has been associated with multipledose aminoglycoside therapy. Nephrotoxic potential is similar among
aminoglycosides and varies according to the frequency of intravenous
admini~tration.~~
Aminoglycosides are potentially toxic to the tubules of
the nephron. After intravenous administration, aminoglycosides saturate
tubular cells. Intracellular aminoglycosides are subsequently pumped
out of the tubular cells, reducing potentially toxic intracellular
concentrations.17,56 Intravenous administration of aminoglycosides by
multidose regimens usually does not permit sufficient time for the
tubular cells to eliminate intracellular aminoglycoside concentrations
before the next dose.112Once-daily intravenous aminoglycoside regimens
have virtually eliminated the nephrotoxic potential of aminoglycosides.lo8Once-daily aminoglycoside therapy should be used whenever
intravenous aminoglycosides are
As with multidose regimens, intravenous aminoglycoside single-dose regimens should be
n,loo, Io2
dosed based on creatinine clearance.7o,
Aminoglycoside-induced tubular dysfunction is best assessed by
urinary cast excretion counts, not by monitoring the serum creatinine.
The serum creatinine is increased for a variety of reasons in many
hospitalized patients and is not a good indicator of tubular function.
Serum creatinine is related to lean body mass in the elderly and is an
indicator of glomerular rather than tubular function. Aminoglycoside
tubular-induced dysfunction usually occurs after about 2 weeks of intravenous aminoglycoside therapy with multiple daily dose regimens.

CI

Ceftriaxone
Temafloxacin

Erythromycin
Nitrofurantoin
Trovafloxacin
Thiabendazole
Nitrofurantoin
Trovafloxacin
Ketoconazole
PAS

Hyperbilirubinemia

Cholestasis

Chronic active hepatitis

Hepatic necrosis, liver
failure

INH
Trovafloxacin
0xacillin

Common

Drug-induced hepatitis
( t serum transaminases)

Side Effects

Table 9. HEPATIC SIDE EFFECTS

F1ucon azo1e
Nitrofurantoin
ddI
ddC

Rifampin
Chloramphenicol
Ketoconazole
Ethionamide
Flucytosine
Delavirdine
Abacavir
Adefovir
Saquinavir
Indinavir
ddI
d4T
ddC
Nevirapine
Crixivan
Abacavir
Adefovir
Linezolid
Chloramphenicol
Tetracycline

Uncommon

Trovafloxacin may cause fatal hepatic necrosis

Trovafloxacin hepatic necrosis is idiosyncratic hypersensitivity
reaction

Erythromycin estolate most common cause of cholestasis, but

other erythromycin formulations also cause cholestasis
Tetracycline hepatoxicity is dose related (e.g., 2 2 g/d)
Doxycycline and minocycline are not hepatoxic

Ceftizoxime in the neonate may result in kemicterus

Most causes of INH hepatitis occur in rapid acetylators during

the first month of antituberculosis therapy
Most t serum transaminases resulting from INH revert to
normal when INH is discontinued. INH should be
discontinued if serum transaminases t 210 X normal
Trovafloxacin may t serum transaminases to 21000 IU/L
after a single dose. Usually serum transaminases 1 rapidly
after trovafloxacin is discontinued
Normalization of t serum transaminases after trovafloxacin
may take days or weeks in patients with pre-existing liver
disease
Nafcillin rarely causes drug-induced hepatitis

Comments

ANTIBIOTIC SIDE EFFECTS

175

There are few reasons to use aminoglycosides for longer than a 2week period. If aminoglycoside therapy is minimized to 2 weeks and if
administered by using a once-daily regimen, aminoglycoside nephrotoxic potential is extremely low.
Vancomycin has little or no nephrotoxic p~tential.'"~
In patients
receiving intravenous vancomycin with increasing serum creatinine, an
explanation should be sought for the elevated serum creatinine. Other
medications being given concurrently with the vancomycin usually are
the cause, but the elevation in the serum creatinine in hospital patients
may be due to a variety of non-drug-related causes (e.g., hypovolemia).
Interstitial Nephritis

Interstitial nephritis may occur with a wide variety of antimicrobials

but is associated most closely with p-lactam therapy.13,90 Acute interstitial
nephritis should not be confused with the nephrotoxic reactions described earlier and are hypersensitivity reactions. Eosinophiluria is a
cardinal finding in antibiotic-induced, acute allergic interstitial nephritis.
Hansen's stain of the urinary sediment is useful diagnostically to show
eosinophiluria. Usually renal function returns after the offending antibiotic is discontinued. Other renal adverse events associated with antimicrobials include crystal formation and are associated most commonly
with acyclovir or indinavir (Table 10).7,s,13
METABOLIC SIDE EFFECTS

Many antibiotics may cause metabolic abnormalities. Commonly

recognized side effects include gonadal and adrenal dysfunction induced
by ketoconazole. Lactic acidosis may accompany abacavir therapy. Hyperglycemia frequently is associated with pentamidine administration.
Gynecomastia, lipodystrophy, and other lipid abnormalities are particularly associated with indinavir but may occur with other protease
inhibitors. Pathophysiology of lipid abnormalities associated with indinavir is not clear because patients have a redistribution of body fat that
may be sufficiently disturbing to the patient to result in cessation of
antiretroviral therapy. Triglyceride elevations may occur secondary to
AZT or ddI therapy. Itraconazole may increase serum triglycerides and
decrease serum aldosterone levels (Table ll)?7
MISCELLANEOUS SIDE EFFECTS

A variety of other side effects have been ascribed to antimicrobials

(Table 12).*Adverse reactions are important from a differential diagnostic and pharmacoeconomic standpoint.
*References 103, 104, 106, 110, 111, 116, 119-121,123, 130-132, 140, 146.

Capreomycin
Aminoglycosides
Polymyxin B
Pentamidine

Acyclovir
Indinavir
P-Lactams

Aminoglycosides

Glomerular toxicity.
Tubular toxicity

Crystal formation

Interstitial nephritis

ATN

ATN = Acute tubular necrosis.

Common

Side Effects

Uncommon

TMP-SMX
Erythromycin
Ciprofloxacin
Nevirapine
Temafloxacin

Sulfonamides (TMP-SMX)

Foscamet
Tetracycline
Capreomycin
Adefovir

Table 10. NEPHROTOXICITY SIDE EFFECTS

Temafloxacin-induced ATN is secondary to autoimmune hemolysis

Aminoglycoside-induced ATN is reversible

Hansens stain of urine (eosinophiluria)is diagnostic

Common with oxacillin but not nafcillin

Foscamet causes nephrogenic diabetes insipidus

Vancomycin is not nephrotoxic
Nephrotoxicity occurring with other nephrotoxic drugs (e.g., vancomycin
plus aminoglycoside combinations) is due to the nonvancomycin
component
Increased fluid intake decreases potential crystal formation

Comments

ANTIBIOTIC SIDE EFFECTS

177

Phlebitis

Phlebitis or phlebitis-like local reactions most commonly are associated with erythromycin, trovafloxacin, and quinupristin/dalfopristin.
Local intravenous site reactions subside rapidly after drug infusion is
terminated.
Arthropathy

Previously, it was thought that quinolones interfered with cartilage

formation with resultant arthropathy in children. It has been shown that
for short courses of quinolone therapy (i.e., 2 to 4 weeks), quinolones do
not cause cartilage dysgenesis or arthropathy. Quinolones may be used
safely in young children.lS, 137
Tendinitis and Tendon Rupture

Tendinitis or tendon rupture has been associated with ciprofloxacin

and is not a quinolone class side effect (see Table 12).137
Skin Discoloration

Skin discoloration may occur after prolonged minocycline use and

may not reverse after discontinuation of t~eatment.3~
SUMMARY

Antibiotic side effects are approached best from an individual agent

perspective rather than from a class-related standpoint. As this article
indicates, with the exception of drug fevers and drug rashes, most
antibiotic side effects are related to individual agents and not class side
effects., 76 Clinicians should view antimicrobial side effects as related to
each organ system and be aware that more often a nonmicrobial medication is the explanation for the drug side effect rather than the antimicrobial. Nonantimicrobial medications are the most common cause of drug
fever; among antimicrobials, p-lactams and sulfonamides are the most
common causes of drug-induced fevers. Antimicrobial side effects have
important implications for the patient, legal and economic implications
for the hospital, and medicolegal implications for the physician. Antibiotic side effects that prolong hospitalization in todays managed care
environment have important economic implications. Clinicians should
be familiar with the most common side effects of the most frequently
used antimicrobials, to minimize the potential of having adverse reactions occur in patients.21.29.38.Q. 45.4651

Common

Ritonavir

T CPK

CpK = Creatine phosphokinase.

AZT
ddI

Ketoconazole
Abacavir
Pentamidine
Ketoconazole
Indinavir
Indinavir
AZT

Myositis
Hyperuricemia

Gonadal function .
Lactic acidosis
Hyperglycemia
J, Cortisol production
Gynecomastia
Lipodystrophy, lipid abnormalities

Side Effects

Table 11. METABOLIC SIDE EFFECTS

~

~~

Adefovir

Ethambutol

Itraconazole

Stavudine

Uncommon

Minimize with increased fluid intake and allopurinol

Ethambutol is the only antituberculosismedication that is not
hepatically inactivated or eliminated

Lipodystrophy may occur with protease inhibitors but is most common

with indinavir
t Triglycerides and J, aldosterone may occur with itraconazole
t Triglycerides may occur with AZT and ddI

Decreased gonadal function may occur with prolonged ketoconazole use

Reversible when drug is discontinued
Transient effect that disappears after infusion

Comments

U
\o

CI

Vancomycin

Amphotericin B

Erythromycin
Trovafloxacin
Clarithromycin
Metronidazole

Ciprofloxacin

Griseofulvin

Quinupristin-dalfopristin

AZT
Foscamet
Ribavirin
TMP-SMX
Nevirapine

Flushing

Fever (nondrug fever)

Local intravenous site

reactions
Metallic taste

Tendinitis, tendon rupture

Glossitis, stomatitis

Arthralgias, myalgias

Rhabdomyolysis
Oral ulcers
Conjunctivitis

SLE = Systemic lupus erythematosus.

Lymphadenopathy

Alopecia

Minocycline
Minocycline
Tetracycline
Ethionamide

Common

Hyperpigmentation
Discolored nails

Side Effects

Table 12. OTHER SIDE EFFECTS

Efavirenz

Aztreonam
ddC
Sulfonamides

TMP-SMX
ddC

Quinupristindalfopristin
Ethambutol
Capreomycin
Etionamide

Lamivudine
(3TC)

Nalidixic acid
AZT

Uncommon

May be severe, may be related to dose/dosing interval

Any antibiotic causing serum sickness or drug-induced SLE can
cause arthralgias or myalgias
Common with AZT; rare with aztreonam
Heals slowly after drug is discontinued
Sulfonamides cause conjunctivitis as part of Stevens-Johnson
syndrome
May occur as part of DRESS syndrome (drug rash, eosinophilia, and
systemic syndromes)

Clarithromycin tastes like aluminum sand in addition to causing taste

perversion
Oral metronidazole frequently is associated with taste perversion
Nearly all quinolone-related tendinitis and tendon ruptures are due
to ciprofloxacin
Heals slowly after drug is discontinued

Usually reversible after drug is discontinued

Red neck or red man syndrome is a transient drug histamine reaction
Amphotericin B regularly causes fever when infused; fever abates
after infusion completed
Local reactions subside after drug infusions

Minocycline discoloration may be permanent

Minocycline discoloration may be permanent. Tetracyclines cause nail
discoloration in young children, not adults
Usually reversible after drug is discontinued

Comments

180

CUNHA

Most adverse events related to antimicrobials are reversible rapidly

on cessation of the medication. Irreversible toxicities include aminoglycoside-induced ototoxicity, Stevens-Johnson syndrome, and toxicity secondary to nitrofurantoin. The most common acute fatal drug reactions
include hypersensitivity reactions resulting in anaphylaxis or the Stevens-Johnson syndrome and fatal hepatic necrosis secondary to trovafloxacin. Clinicians should eliminate the use of drugs associated with
chronic or fatal toxicities because multiple therapeutic alternatives exist
for virtually every potential infection.
References
1. Ackerman BH, Bradsher RW Vancomycin and red necks. Ann Intem Med 102:724,
1985
2. Adam D, Von Rosenstiel N Adverse reactions to quinolones, potential toxicities, drug
interactions, and metabolic effects. Infect Dis Clin Pract 3(suppl 3):S177, 1994
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